European Journal of Clinical Pharmacology (2019) 75:1431–1443

https://doi.org/10.1007/s00228-019-02713-1

PHARMACOEPIDEMIOLOGY AND PRESCRIPTION

Fluoroquinolones and the risk of tendon injury: a systematic

review and meta-analysis
Carlos Alves 1,2 & Diogo Mendes 2 & Francisco Batel Marques 1,2

Received: 15 May 2019 / Accepted: 25 June 2019 / Published online: 4 July 2019
# Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
Purpose Tendinopathy is a known adverse reaction associated to fluoroquinolones, but a meta-analysis was not yet published.
The aim of this study was to conduct a systematic review and a meta-analysis of the scientific evidence evaluating the risk of
tendon injury associated with fluoroquinolones.
Methods A literature search was conducted to identify observational studies which reported results on the risk of Achilles tendon
rupture (ATR), risk of Achilles tendinitis (AT), or risk of any tendon disorders (ATD). A meta-analysis was performed by pooling
odds ratios (ORs) with their 95% confidence intervals (CIs).
Results Fifteen studies were included in the meta-analysis. Treatment with fluoroquinolones was associated with an increased
risk of ATR (OR 2.52 (95% CI 1.81–3.52), p < 0.001, I2 = 76.7%), an increased risk of AT (OR 3.95 (95% CI 3.11–5.01),
p < 0.001, I2 = 0%), and increased risk of ATD (OR 1.98 (95% CI 1.62–2.43), p < 0.001, I2 = 84.5%). The initial risk estimates
remained statistically significant among patients aged ≥ 60 years old. Risk estimates did not significantly change after depending
on the concomitant use of corticosteroids or studies methodological quality assessment. The analysis according to the type of
fluoroquinolones was only possible for ATR, which were ofloxacin and norfloxacin were found to increase the risk of this
outcome, but not ciprofloxacin and levofloxacin.
Conclusions The results of this meta-analysis confirm the risk of tendon injuries associated with fluoroquinolones. Older age and
concomitant use of corticosteroids seem to be additional risk factors for tendinopathy.

Keywords Fluoroquinolones . Tendinopathy . Pharmacovigilance . Risk assessment . Meta-analysis

Introduction bioavailability and are generally well tolerated [2].

Systemic fluoroquinolones are commonly used antibiotics,
presenting excellent potency in vitro against most
Enterobacteriaceae, fastidious gram-negative bacilli in-
cluding species of Haemophilus and gram-negative cocci
[1]. When administered orally, fluoroquinolones have good
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00228-019-02713-1) contains supplementary
material, which is available to authorized users.
* Carlos Alves
carlosmiguel.costaalves@gmail.com
1
Laboratory of Social Pharmacy and Public Health, School of
Pharmacy, University of Coimbra, Coimbra, Portugal
2
AIBILI – Association for Innovation and Biomedical Research on
Light and Image, CHAD – Centre for Health Technology
Assessment and Drug Research, Coimbra Regional
Pharmacovigilance Unit (UFC), Coimbra, Portugal
However, over the years, the use of fluoroquinolones has
been associated with serious adverse reactions, leading to
the market withdrawal of some of these antibiotics, such as
temafloxacin (severe hemolytic–uremic syndrome),
trovafloxacin (hepatotoxicity), grepafloxacin (QT interval
lengthening), and gatifloxacin (dysglycemia) [2–4].
Although rare, tendon injury is a serious adverse ef-
fect of systemic fluoroquinolones. In 1995, the US Food
and Drug Administration (US FDA) recommended an
update of the labeling of all marketed systemic
fluoroquinolones to include a warning about the possi-
bility of tendon rupture [5]. In 2008, a boxed warning
citing an increased risk of tendinitis and tendon rupture
was added to the labeling of systemic fluoroquinolones,
based on evidence from post-marketing spontaneous re-
ports and observational studies [6]. The risk of such
adverse effects is further increased in patients aged over
60, in transplant recipients, and among individuals on
steroid therapy [7].
1432
In 2016, the US FDA reinforced warnings about the risk of
tendinopathies associated with the use of systemic
fluoroquinolones [6]. Since the risk of these serious adverse
effects may outweigh the benefits of systemic
fluoroquinolones in the treatment of minor infections, these
antibiotics should be reserved for use when no alternative
treatment options can be considered [6]. In 2018, the
European Medicines Agency (EMA) also recommended
new restrictions on the use of systemic fluoroquinolones after
reviewing safety information about disabling and potentially
long-lasting adverse effects, including tendon injuries [8, 9].
Some systematic reviews of studies evaluating the
risk of tendinopathies associated with the use of system-
atic fluoroquinolones have been carried out [2, 10–12].
However, important limitations seem to characterize
those works. Not all the observational studies available
in the scientific literature were conducted in the previ-
ous systematic reviews, particularly the most recently
published evidence [9, 13–15]. Moreover, although a
meta-analysis has been conducted, the results were not
stratified according to the different outcomes assessed in
the epidemiological studies, different risk windows,
studies methodological quality, or type of comparators
used [12].
Since fluoroquinolones are essential medicines, it is
important, from a public health perspective, to evaluate
the consistency of the results from observational studies
assessing the risk of tendinopathies. Although meta-
analyses may have some limitations, quantitative synthesis
is usually preferred over qualitative analysis of the results
of a set of studies [16]. Moreover, conducting a meta-
analysis may allow assessing the consistency of the results
and understanding the influence of risk factors and addi-
tional variables in the risk of tendinopathies associated
with the use of fluoroquinolones [17, 18].
The aim of this systematic review and meta-analysis is to
assess the risk of tendon injuries associated with the use of
systemic fluoroquinolones, as well as to explore risk varia-
tions due to risk factors, study designs, and methodological
quality of included studies.
Methods
The current systematic review and meta-analysis were report-
ed according to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) statement [19].
Literature search
PUBMED, EMBASE, and Cochrane Library were searched
from its inception until November 2018 in order to identify
relevant studies evaluating the risk for tendon injury
Eur J Clin Pharmacol (2019) 75:1431–1443
associated with systemic fluoroquinolones. MeSH and
Emtree terms, the MedDRA dictionary (v.21.0), and the
International Nonproprietary Names (INN) of
fluoroquinolones were used in the search equation [20–22].
Only the literature published in the English language was
considered for inclusion. Bibliographic references list of all
relevant studies, meta-analyses, and systematic reviews were
hand searched in order to identify additional eligible articles.
We did not seek to identify safety data of fluoroquinolones
beyond published studies. The electronic databases search
strategy is available in Supplemental Table 1.
Study selection, data extraction, and quality
assessment
The titles and abstracts of all retrieved citations were screened
by two independent reviewers (C.A. and D.M.) to identify
potentially relevant publications. Full texts were retrieved for
relevant citations. Discrepancies were resolved by majority
decision (two out of three) involving a third investigator
(F.B.M.). Studies would be included if they fulfilled the fol-
lowing criteria: 1, being a comparative observational study
(case-control or cohort studies); 2, included patients of all ages
and genders; 3, compared fluoroquinolones with a placebo (or
non-use) or active control; and 4, have provided risk estimates
(relative risk (RR), odds ratio (OR), or hazard ratio (HR)) or
data allowing to calculate such risk estimates. Only peer-
reviewed full papers were considered. Basic science studies,
reviews, case reports, and studies without a comparison group
were excluded.
The following data from the studies was extracted: design,
characteristics of participants, treatments under evaluation,
risk-window length, and estimated effect measures.
Studies’ methodological quality was assessed through
Newcastle–Ottawa scale, which considers the following char-
acteristics: selection of the study groups, comparability of the
groups, ascertainment of either the exposure (for case-control
studies), or outcome of interest (for cohort studies) [23]. A
maximum of one point for each item within the “Selection”
and “Exposure/Outcome” categories could be awarded. For
“Comparability” category, a maximum of two points could
be awarded. The summary score equals the number of points
earned by each study, totaling a maximum of 9 points. Studies
scoring ≥ 8 points were considered to be of good quality, those
scoring < 8 and ≥ 6 points were of moderate quality, and those
scoring < 6 points were considered to have poor quality. Two
independent reviewers assessed the methodological quality of
the studies (C.A. and D.M.). A third investigator (F.B.M.)
helped to resolve discrepancies by majority decision. When
more than one reference was found for the same study, the
methodological quality evaluation was based on the total set
of information.
Eur J Clin Pharmacol (2019) 75:1431–1443
Outcomes assessed
The following outcomes were assessed in this meta-analysis:
risk of Achilles tendon rupture (ATR), risk of Achilles tendi-
nitis (AT), and risk of any tendon disorders (ATD). The out-
comes selected for this systematic review and meta-analysis
were the same as those considered in a previous systematic
review [10]. The ATR and AT are the most frequently evalu-
ated tendon injury outcomes in published studies. The ATD is
a composite outcome of any tendon rupture and/or any
tendinitis.
Statistical analysis
A meta-analysis was performed by pooling odds ratios (ORs)
with their 95% confidence intervals (CIs), using the
DerSimonian and Laird random-effects model [24]. This
model was chosen since the validity of tests of heterogeneity
can be limited with a small number of component studies and
it is more conservative than a fixed effect model in the pres-
ence of between-studies heterogeneity. If the studies presented
more than one risk estimate, the most adjusted one would be
used. The effect size estimates available for the shortest time
intervals between fluoroquinolones prescription and tendon
injury diagnosis or treatment were used in the overall risk
estimate. The I2 statistic test was used to assess heterogeneity
between studies. An I2 estimate > 50% was considered indic-
ative of substantial heterogeneity [25]. The publication bias
was visually examined by a funnel plot and statistically eval-
uated by Egger’s regression asymmetry test [26].
A sensitivity analysis was conducted to explore the influ-
ence of the following variables on the summary estimates:
study designs, studies’ methodological quality scores, risk
windows defined in included studies, age (≥ 60 vs. < 60 years
old), type of fluoroquinolone, corticosteroid use, kidney dis-
ease, and comparator (fluoroquinolone non-users vs. active
comparator). Risk window is the period of time considered
after the end of fluoroquinolone treatment course during
which patients are at risk of suffering tendon injuries. The
influence of each individual study in overall risk estimate
was assessed using the “one-study removed” analysis. All
reported p values are 2-sided with significance being set as
less than 0.05. Stata (version 13.1) was used to perform
statistics.
Results
Figure 1 presents the flow of the search strategy criteria.
The electronic databases searched returned 1612 refer-
ences. After excluding duplicates and other studies with
inadequate design, 15 studies were included in this meta-
1433
analysis comprising seven cohort studies [15, 27–32] and
eight case-control studies [9, 13, 14, 33–37].
Studies characteristics
The main characteristics of the studies are presented in
Table 1. Study design, participants’ demographic characteris-
tics, drugs under evaluation, and a number of subjects evalu-
ated were described. Patients’ mean age varied from 43.5 to
65.0 years and the proportion of female patients included in
the studies ranged from 22.1 to 71.4%. Most of the studies
elected the population sample from either prescription dis-
pensing data, health administrative data, or general practice
data, although one study examined a post-transplant popula-
tion (heart) and one study evaluated patients with end-stage
renal disease [30, 32]. Only one study used propensity score to
match participants [31], while the remaining adjusted the anal-
yses for several variables. Five studies compared the risk of
tendon injuries in fluoroquinolone users with active controls
(other antibiotics), while the remaining compared fluoroquin-
olone users with non-users [15, 27–29, 31]. Thirteen studies
defined a risk window of 30 days between fluoroquinolone
exposure and outcome development. Two studies adopted a
90-days risk period and the other two did not report the length
of time during which the outcome was assessed. Nine studies
assessed the risk of ATR, three the risk of AT, and eight the
risk of ATD.
The results of the assessment of studies’ methodological
quality are also presented in Table 1. The methodological
quality was assessed as “good” for three studies, “moderate”
for nine, and “poor” for three. Lack of information on con-
founding variables used to adjust risk estimates was the main
methodological impairment found among these studies.
Risk for tendon injuries
The treatment with fluoroquinolones was associated with an
increased risk of ATR (9 studies, OR 2.52 (95% CI 1.81–
3 . 5 2 ) , p < 0 . 0 0 1 , I 2 = 7 6 . 7 % ) ( F i g . 2 ; Ta b l e 2 ) .
Fluoroquinolones were also associated with an increased risk
of AT (3 studies, OR 3.95 (95% CI 3.11–5.01), p < 0.001, I2 =
0%) and of ATD (8 studies, OR 1.98 (95% CI 1.62–2.43),
p < 0.001, I2 = 84.5%) (Fig. 3 and Fig. 4, respectively). The
risk estimates did not significantly change when the analysis
was stratified according to different study designs, with the
exception of the risk of AT among cohort studies (1 study, OR
3.70 (95% CI 0.90–15.16), p = 0.069). The increased risk of
all three outcomes remained statistically increased among
older patients (aged ≥ 60 years) when the analysis was strati-
fied by age. The risks estimated for any of the three outcomes
did not significantly change irrespective of the concomitant
use of corticosteroids and fluoroquinolones.
1434 Eur J Clin Pharmacol (2019) 75:1431–1443

Identification
1612 potentially relevant articles Relevant studies found by hand search
(PUBMED, n=426; EMBASE, n=1153; of reference lists
COCHRANE LIBRARY, n=33) (n = 0)

Records after duplicates removed

(n = 694)
Screening

Records screened Articles excluded after

(n = 694) titles/abstracts revision (n = 664)

15 full-text articles excluded:

Full-text articles assessed for Cross-sectional, n = 6
Eligibility

eligibility (n = 30) Systematic reviews, n = 7

Cohort = 2 (did not report sufficient data)

Studies included in qualitative

synthesis; n=15
Included

15 studies included in the

meta-analysis

Fig. 1 PRISMA flow diagram

It was not possible to stratify the results according to
renal failure status, since only two studies assessed the
risk of tendinopathy associated with fluoroquinolones in
patients with renal insufficiency, one considering a differ-
ent outcome from the other (ATR vs. AT) [30, 35]. One
identified an increased risk of AT (OR 20.0, 95% CI 2.7–
149) and the other increased risk of ATR (RR 1.65, 95%
CI 1.32–1.84) [30, 35].
The risk of AT did not significantly change when the
analysis was conducted according to the methodological
quality of the studies (Table 2). The risk of ATR remained
increased, with statistical significance, among the studies
with “moderate” methodological quality. Among the stud-
ies with “good” methodological quality, the risk of ATR
became statistically non-significant but associated with
high heterogeneity (OR 1.94, 95% CI 0.76–4.99, p =
0.147, I2 = 91.0%). The risk of ATD became statistically
non-significant when only studies with “poor” methodo-
logical quality were considered (OR 3.04, 95% CI 0.68–
13.52, p = 0.144, I2 = 72.0%).
No statistically significant result was identified among the
studies evaluating the risk of ATR more than 30 days after the
fluoroquinolone prescription (OR 1.72, 95% CI 0.70–4.25,
p = 0.238, I2 = 18.2%) (Table 2). The initial ATR risk estimate
did not significantly change among the studies considering a
30-day at-risk window after the fluoroquinolone prescription.
When comparing fluoroquinolone users with non-users,
the initial increased risk estimates remained statistically sig-
nificant (Table 2). Only one study compared fluoroquinolones
with an active comparator for both ATR and AT risk analyses
(Table 2). The initial ATD risk estimate did not significantly
change when the analysis was stratified by different
comparators.
The stratification of the risk estimates according to the
types of fluoroquinolones was only possible for the outcome
ATR (Table 2). Ofloxacin and norfloxacin were associated
with an increased risk of ATR, but not ciprofloxacin and
levofloxacin. For AT and ATD, no sufficient data was avail-
able to stratify the results according to the type of
fluoroquinolone.
Table 1 Characteristics of the studies included
Study
van der Linden et al. 1999
Sode et al. 2007
Barge-Caballero et al. 2008
Hori et al. 2012
Daneman et al. 2015
Humbyrd et al. 2018
Jupiter et al. 2018
van der Linden et al. 2002
van der Linden et al. 2003
Study design Population Studied interventions
Intervention/cases Control
Retrospective cohort study Patients, aged at least 15 years old, living in The Netherlands, whose data Fluoroquinolone Reference group: amoxicillin,
was collected from 41 general practices in the period from January 1, trimethoprim, cotrimoxazole, or
1995 until December 31, 1996. All individuals treated with either nitrofurantoin
fluoroquinolones, amoxicillin, trimethoprim, cotrimoxazole, or
nitrofurantoin were followed from the first day of treatment until the
outcome of interest, death, transfer to another practice, or end of the
study period, whichever came first.
Eur J Clin Pharmacol (2019) 75:1431–1443
Retrospective cohort study Patients living at Funen County, Denmark, with data on Achilles tendon Fluoroquinolone Reference group: tetracyclines,
ruptures and fluoroquinolones, tetracyclines, penicillins, cephalosporins, penicillins, cephalosporins,
sulfonamides, macrolides, aminoglycosides, and glycopeptides use sulfonamides, macrolides,
retrieved from three population-based databases which included aminoglycosides, or
information on residents in primary and secondary care during the period glycopeptides
1991–1999.
Retrospective cohort study Adult patients, aged at least 18 years old, submitted to heart transplantation Levofloxacin Levofloxacin non-use
in a Spanish hospital and prescribed with fluoroquinolones, with data
collected from August 1995 to September 2006
Retrospective cohort study Patients prescribed with fluoroquinolones or cephalosporins in Japan from Fluoroquinolone Cephalosporin
April 1996 to December 2009 were identified and considered for
inclusion in the study. Diagnosis of tendon disorder after
fluoroquinolone or cephalosporin administration was identified by an
automatic search of the hospital medical records.
Retrospective cohort study The Ontario Registered Persons Database was used to identify adult Fluoroquinolone Amoxicillin
patients from Ontario, Canada, turning age 65 between April 1, 1997,
and March 31, 2012 were followed until primary outcome, death or end
of follow-up course.
Retrospective cohort study Patients with end-stage renal disease (ESRD) using Medicare parts A and B Fluoroquinolone Fluoroquinolone non-use
(USA) as their primary health insurance between January 1, 1999, and
December 31, 2013. All patients were studied from their development of
ESRD until death, end of Medicare primary coverage, or end of the
study.
Retrospective cohort study Adult patients aged 18 to 90 years with at least one index prescription of Fluoroquinolone Fluoroquinolone non-use
fluoroquinolone between January 1, 2009, and June 30, 2014. Data was Reference group*
retrieved from Clinfomatics DataMart, USA. Propensity scores were
used to match fluoroquinolone users with other antibiotic users and
antibiotic non-users.
Case-control study Patients aged 18 years or over who had received a fluoroquinolone and had Diagnosis of ATR, AT, –
clinical data on IMS Health database, UK (July 1, 1992 to June 30, and ATD
1998). Potential cases were identified by reviewing patient profiles and
clinical data and excluded tendon disorders due to direct trauma. A group
of 10,000 control patients from the study cohort was randomly selected.
Case-control study Data was retrieved from the General Practice Research Database, UK, Diagnosis of ATR –
considering a period from 1988 to 1998. Cases were defined as all
persons who had an Achilles tendon rupture and who had at least
18 months of valid medical history before the index date. A group of
1435
Table 1 (continued)
1436

50,000 randomly selected patients with at least 18 months of valid

Seeger et al. 2006
Corrao et al. 2006
Wise et al. 2012
Nyyssönen et al. 2018
Morales et al. 2018
Persson and Jick, 2019
history who were assigned a random date as index date was included as
control.
Case-control study Study included data from patients registered at the Ingenix Research Diagnosis of ATR and a –
Database, USA. Cases were persons with both a diagnosis and procedure procedure for ATR.
(either surgical or non-surgical) related to ATR occurring between
January 1, 1997, and June 30, 2001. Controls were randomly sampled
persons by calendar day with replacement in a ratio of 20:1.
Case-control study Study was performed by retrieving data from automated health databases Diagnosis of ATR and –
from the Region of Lombardia, Italy. Cases were defined as patients aged ATD
18 years or over who had a hospital discharge diagnosis of
non-traumatic tendinitis in 2002–2003. Controls were randomly selected
among those eligible for inclusion in the study in a ratio of 5:1.
Case-control study Data was retrieved from The Health Improvement Network (THIN) Diagnosis of AT –
database, UK. All subjects who had a first-time diagnosis of Achilles
tendonitis between January 1, 1986, and November 31, 2009 were
identified. For each subject, a case period as the 30 days immediately
before the diagnosis date, and a control period as the 30 days 1 year
before the diagnosis date were defined.
Case-control study Data was collected from the Finnish Hospital Discharge Register. Cases Diagnosis of ATR –
were defined as patients admitted in hospital with Achilles tendon
rupture during the years 1998–1999. Randomly selected age- and
sex-matched controls from the Finnish population registry were used for
comparison.
Nested case-control study Adults aged at least 18 years or over identified in THIN database, UK, Diagnosis of ATR –
between January 1, 1999, and December 31, 2015. The date of the first
event occurring after cohort entry was the index date for case subjects.
Controls were randomly selected and matched to cases in a ratio of 4:1.
Nested case-control study The study included all patients who were registered in the UK Clinical Diagnosis of ATR –
Practice Research Datalink (CPRD) Gold, between 1990 and 2015.
Cases were patients with a diagnosis of tendon rupture identified using
Read codes. Up to 4 controls were matched to each case.

Study Risk period (days) Age mean (years) Female (%) Patients (n, ID/C) Outcomes/fluoroquinolone M.Q.
use (n, ID/C)*

van der Linden et al. 1999 30 days Fluo 53.0 Fluo 63.9 1841/9406 AT 4/4 7
Ref 45.0 Ref 71.4
Sode et al. 2007 90 days 44.2 25.0 28,262/401080 ATR 5/21 6
Barge-Caballero et al. 2008 30 days 58.8 22.1 149 ATD 14 3
Hori et al. 2012 30 days NR NR 17,147/38517 ATD 14/5 4
Daneman et al. 2015 30 days Fluo 65 Fluo 51.4 657,950/1,086,410 ATD 23028/14123 6
Amox 65 Amox 51.1
Humbyrd et al. 2018 NR NR 55.0 NR ATR: NR 5
Jupiter et al. 2018 30 days Fluo 43.5 Fluo 52.4 576,318/576,318/631304* ATD 550/323/551* 8
Non-U 43.8 Non-U 52.3
Ref 43.7 Ref NR
Eur J Clin Pharmacol (2019) 75:1431–1443
Eur J Clin Pharmacol (2019) 75:1431–1443 1437

ID, intervention drug; C, control; M.Q., methodological quality assessment; ATD, any tendon disorder; AT, Achilles tendinitis; ATR, Achilles tendon rupture; Fluo, fluoroquinolone; Ref, reference group;
Amox, amoxicillin; NR, not reported; ESRD, end-stage renal disease; USA, United States of America; UK, United Kingdom; THIN, The Health Improvement Network; CPRD, Clinical Practice Research
Among the results identified for the three outcomes, the

6
8
7

7
7

7
“one-study removed” analysis indicates that the overall risk
estimates did not significantly change when each study was
individually removed from the meta-analysis (Supplemental
Figs. 1, 2, and 3).

ATD 160/432 Publication bias

ATD 111/236

ATD 85/178
ATD 49/298

Egger’s asymmetry test was not statistically significant for the

ATR 14/100

ATR 29/448

ATR 42/21
ATR 67/82

ATR 41/19
ATR 3/124

AT 267/77
AT 43/298

ATR 6/10

outcomes AT and ATD. Evidence of small-study effects was

identified among the studies assessing the risk of ATR (p =
0.024). Subjective evaluation of publication bias was based on
the visual inspection of the funnel plot. Most studies did iden-
tify increased risk estimates for the three outcomes, although
studies with less precise risk estimates have been identified as
well (Supplemental Figs. 4, 5, and 6).
22,194/104,906

28,907/28,907
1367/50,000

4836/18356

3802/14002
947/18,940
742/10,000

Discussion
1118/1118

The benefits of antibiotic therapy with systemically adminis-

tered fluoroquinolones are well recognized. However, the use
of this class of antibiotics is associated with rare but serious
adverse effects that may result in significant impairment of
Controls 39.0

Controls 36.3
Controls 52.0

Controls: NR
Controls: NR

patients, namely tendinitis and tendon rupture, particularly

Cases 35.9
Cases 63.5

Cases 38.8
Cases 61.0

Cases 30.6

of the Achilles tendon. Despite being known for some time,

21.0

the risk of tendon injuries associated with fluoroquinolones

NR

NR

has been continuously investigated by the scientific commu-

n i t y, m a i n l y t h r o u g h t h e c o n d u c t i o n o f s e v e r a l
pharmacoepidemiological studies [9, 13, 15]. Moreover,
EMA and US FDA have recently recommended reinforcing
the restriction of the use of fluoroquinolones due to their dis-
Controls 61.3
Controls: NR

Controls: NR
Controls: NR

Controls 47

Cases 55.9
Cases 56.0

Cases 61.6
Cases 46.5

abling and potentially permanent adverse effects involving

Cases 48

muscles, tendons or joints, and the nervous system [6, 8, 9].

44.1

NR
NR

This systematic review and meta-analysis identified increased

risks of ATR, AT, and ATD associated with fluoroquinolones.
The findings are in line with the current knowledge about the
safety profile of these drugs.
The mechanism of tendon injury associated with
fluoroquinolones is not well clarified but appears to be multi-
factorial and may result from direct toxicity and degenerative
30 days
90 days
30 days

30 days
30 days

30 days

30 days

changes in collagen fibers [10, 28]. It was demonstrated that

NR

fluoroquinolones can enhance matrix metalloproteinase ex-

pression and the inhibition of both fibroblasts proliferation
and the synthesis of the matrix, which can result in the devel-
opment of tendinopathies [38, 39]. A study conducted in dogs
van der Linden et al. 2002

van der Linden et al. 2003

assessed the hypothesis of fluoroquinolones having chelate

Persson and Jick, 2019
Nyyssönen et al. 2018

properties [40]. The findings suggested that fluoroquinolone-

Table 1 (continued)

Morales et al. 2018

induced toxic effects on connective tissues may be due to the

Corrao et al. 2006
Seeger et al. 2006

Wise et al. 2012

magnesium-antagonistic effects of these antibiotics [40].

A d d i t i o n a l l y, t h e r e i s e v i d e n c e s u p p o r t i n g t h a t
Datalink

fluoroquinolone-associated tendinopathy may result from ox-

idative stress induction [41].
1438
Fig. 2 Forest plot of the risk of
ATR associated with Seeger 2006
fluoroquinolones
Corrao 2006
vanderLinden 2002
vanderLinden 2003
Nyyssonenn 2018
Sode 2007
Humbyrd 2018
Morales 2018
Persson 2019
Overall (I-squared = 76.7%, p = 0.000)
NOTE: Weights are from random effects analysis
.034
According to this meta-analysis, patients aged ≥ 60 years
old are at an increased risk for ATR and AT. These results are
in line with previous warnings issued by regulatory authori-
ties, which recommended that fluoroquinolones should be
used with special caution in older patients [6, 8]. The influence
of concomitant use of corticosteroids on the risk of tendon
injury in patients treated with fluoroquinolones was also eval-
uated in some pharmacoepidemiological studies. According
to the sensitivity analysis, it was observed an increase in risk
sizes between 4.68-fold (ATD) and 14.72-fold (ATR) for the
three outcomes among patients simultaneously using
fluoroquinolones and corticosteroids, compared with the ini-
tial estimates. Therefore, the combination of these drugs
should be avoided, as previously recommended by drug reg-
ulatory agencies [6, 8].
The observational studies included in this meta-analysis
presented varying demographic characteristics and methodol-
ogies. Two cohort studies investigating the risk of tendon in-
juries associated with fluoroquinolones included heart
transplanted patients and end-stage renal disease patients
[30, 32]. It has been suggested that individuals submitted to
organ transplant and patients with renal insufficiency are at
greater risk of suffering tendon injuries, particularly Achilles
tendon ruptures and tendinitis [30, 32]. Gender distribution of
the population samples was significantly different among the
studies. There is conflicting evidence regarding the influence
of patients’ sex in the risk of tendon injuries. There are studies
suggesting that one specific gender, male or female, may be a
risk factor for tendon injury, while others have not [33–35].
Although renal impairment is a known risk factor for tendon
injury, it was not possible to conduct a sensitivity analysis due
Eur J Clin Pharmacol (2019) 75:1431–1443
1.20 (0.80, 1.80)
4.10 (1.78, 9.47)
7.10 (1.72, 29.37)
4.30 (2.39, 7.75)
2.20 (1.28, 3.77)
3.10 (1.15, 8.38)
1.56 (1.32, 1.84)
3.14 (2.12, 4.66)
2.71 (1.76, 4.17)
2.52 (1.81, 3.52)
1 29.4
to the scarcity of data. Only two studies assessed the risk of
tendinopathy associated with fluoroquinolones in patients suf-
fering from renal insufficiency, but considered two different
outcomes (ATR vs. AT), precluding a quantitative synthesis of
the results [30, 35].
Most of the studies assessing the risk of ATR due to
fluoroquinolones included in this meta-analysis considered
risk-window periods of 30 days. Yet, two studies assumed
risk-window periods of 90 days and two other studies did
not report the length of time during which patients were con-
sidered to be at risk. The sensitivity analysis demonstrated that
the risk of ATR remained statistically increased when the
analysis was restricted to studies considering a 30-day risk
window, but not among those considering a risk period of
90 days. A systematic review of case reports concluded that
40% of the cases of tendon rupture were diagnosed within the
first 6 days after treatment initiation, while the mean time to
onset was estimated at 26 days [2]. Additionally, half of the
cases of tendinitis occurred within the first 6 days of treatment
and the mean time to onset of symptoms after the initiation of
fluoroquinolone therapy was 18 days [2]. The studies included
in this meta-analysis assessed the risk of AT and ATD within a
risk period of 30 days.
The control groups used by the observational studies
included in this meta-analysis differed as well. Although
non-use of fluoroquinolones was the most common com-
parator group, four cohort studies used active controls [15,
27–29]. Noteworthy, it is possible that observational stud-
ies using fluoroquinolone non-users as control groups may
have been affected by confounding-by-indication, namely
if the infections were causally related to the tendon injuries
Eur J Clin Pharmacol (2019) 75:1431–1443 1439

Table 2 Odds ratios (OR) and

95% CIs of tendon injury Studies Odds ratio (OR) Heterogeneity
associated with fluoroquinolones
n 95% CI p I2

Outcome
Achilles tendon rupture 9 2.52 (1.81–3.52) < 0.001 76.7%
Achilles tendinitis 3 3.95 (3.11–5.01) < 0.001 0.0%
Any tendon disorders 8 1.98 (1.62–2.43) < 0.001 84.5%
Age
Achilles tendon rupture
< 60 years 3 1.71 (0.92–3.17) 0.088 16.0%
≥ 60 years 4 3.61 (1.21–10.79) 0.022 83.8%
Achilles tendinitis
< 60 years 2 1.35 (0.87–2.10) 0.180 31.8%
≥ 60 years 2 5.08 (1.93–13.33) 0.001 89.9%
Any tendon disorders
< 60 years 4 1.28 (1.11–1.49) 0.001 47.4%
≥ 60 years 4 2.17 (1.48–3.20) < 0.001 94.6%
Corticosteroid use
Achilles tendon rupture
Yes 5 14.72 (8.83–24.53) < 0.001 0.0%
No 4 2.27 (1.21–4.27) 0.011 59.2%
Achilles tendinitis
Yes 1 9.10 (4.60–18.00) < 0.001 –
No 1 3.20 (2.31–4.43) < 0.001 –
Any tendon disorders
Yes 4 4.68 (2.32–9.45) < 0.001 84.1%
No 2 1.56 (1.22–1.99) < 0.001 54.8%
Study designs
Achilles tendon rupture
Case controls 7 2.76 (1.86–4.08) < 0.001 71.3%
Cohorts 2 1.83 (1.04–3.24) 0.037 43.9%
Achilles tendinitis
Case controls 2 3.85 (2.75–5.37) < 0.001 41.6%
Cohorts 1 3.70 (0.90–15.16) 0.069 –
Any tendon disorders
Case controls 4 1.83 (1.46–2.30) < 0.001 65.6%
Cohorts 4 2.18 (1.57–3.02) < 0.001 87.4%
Methodological quality assessment
Achilles tendon rupture
Good methodological quality 2 1.94 (0.76–4.99) 0.167 91.0%
Moderate methodological quality 6 3.07 (2.36–3.98) < 0.001 0.0%
Poor methodological quality 1 1.56 (1.32–1.84) – –
Achilles tendinitis
Good methodological quality 0 – – –
Moderate methodological quality 3 3.95 (3.11–5.01) < 0.001 0.0%
Poor methodological quality 0 – – –
Any tendon disorder
Good methodological quality 2 1.68 (1.49–1.90) < 0.001 0.0%
Moderate methodological quality 4 2.08 (1.60–2.70) < 0.001 86.1%
Poor methodological quality 2 3.04 (0.68–13.52) 0.144 72.0%
1440 Eur J Clin Pharmacol (2019) 75:1431–1443

Table 2 (continued)
Studies Odds ratio (OR) Heterogeneity

n 95% CI p I2

Type of fluoroquinolone
Achilles tendon rupture
Ofloxacin 3 2.84 (1.31–6.19) 0.008 0.0%
Levofloxacin 1 0.60 (0.35–1.04) 0.069 –
Ciprofloxacin 3 1.34 (0.91–1.97) 0.138 0.0%
Norfloxacin 2 3.02 (1.32–6.93) 0.039 0.0%
Risk window
Achilles tendon rupture
≤ 30 days 5 3.32 (2.59–4.28) < 0.001 0.0%
> 30 days 2 1.72 (0.70–4.25) 0.238 66.7%
NR 2 1.68 (1.27–2.21) < 0.001 30.0%
Achilles tendinitis
≤ 30 days 3 3.95 (3.11–5.01) < 0.001 0.0%
> 30 days 0 – – –
NR 0 – – –
Any tendon disorder
≤ 30 days 8 1.98 (1.62–2.43) < 0.001 84.5%
> 30 days 0 – – –
NR 0 – – –
Comparator
Achilles tendon rupture
Fluoroquinolone non-users 8 1.58 (1.27–1.96) < 0.001 0.0%
Active comparator 1 3.10 (0.13–72.34) 0.481 –
Achilles tendinitis
Fluoroquinolone non-users 2 3.77 (1.48–9.57) 0.005 0.0%
Active comparator 1 3.70 (0.003–483.70) 0.718 –
Any tendon disorder*
Fluoroquinolone non-users 7 1.88 (1.57–2.24) < 0.001 41.4%
Active comparator 2 1.18 (1.03–1.35) 0.016 0.0%
Data source
Achilles tendon rupture# 7 2.28 (1.57–3.30) < 0.001 74.2%
Achilles tendinitis 3 3.95 (3.11–5.01) < 0.001 0.0%
Any tendon disorders$ 7 2.06 (1.65–2.56) < 0.001 85.2%

*One study (Jupiter et al. 2018) assessed the risk of ATD associated with fluoroquinolones vs. non-users and vs.
active comparator
#
van der Linden et al. (2003) (MQ score 7) and Persson and Jick (MQ score 7) were removed from the analysis
because their data source overlapped with van der Linden et al. (2002) (MQ score 7) and Morales et al. (2018)
(MQ score 8), respectively (Note that although van der Linden et al. (2002) and van der Linden et al. (2003) both
have the same MQ score, the 2003 publication was removed because it is the most recent one)
$
Persson and Jick was removed from the analysis because the data source overlapped with Morales et al. (2018)

events [15]. Therefore, some authors established compari-
sons with active controls. Yet, the studies included in this
meta-analysis used different antibiotics as active controls.
Some compared fluoroquinolone users with a composite of
multiple antibiotics, such as nitrofurantoin, amoxicillin,
tetracyclines, and trimethoprim, which are mostly indicat-
ed to treat mild urinary tract infections [15, 27, 28]. Two
studies used antibiotics as negative controls in order to
assess the specificity of the association between
fluoroquinolones and tendinopathy [9, 15]. Nevertheless,
the risk of tendon injuries seems to increase due to
fluoroquinolones use, regardless of the chosen comparator.
Only three out of the 15 studies were assessed as having
“good” methodological quality. Most of them did not take into
Eur J Clin Pharmacol (2019) 75:1431–1443 1441

Wise 2012 4.40 (3.30, 5.87)

vanderLinden 2002 3.10 (2.00, 4.80)

vanderLinden 1999 3.70 (0.90, 15.16)

Overall (I-squared = 0.0%, p = 0.423) 3.95 (3.11, 5.01)

NOTE: Weights are from random effects analysis

.066 1 15.2

Fig. 3 Forest plot of the risk of AT associated with fluoroquinolones

account all the factors known to modify the risk of tendon
injuries, such as trauma, transplant, obesity, diabetes mellitus,
kidney failure, or recreational sports. The reduced risk of con-
founding was deemed to be important in order to attain higher
methodological scores. These may have been the reason why
previous systematic reviews using the same methodological
quality assessment tool awarded higher scores to some of the
studies that were also included in this systematic review and
meta-analysis [10, 12].
The systematic review and meta-analysis conducted by
Yu and colleagues (2019) have identified an increased risk
of tendinopathy associated with fluoroquinolones as well
[12]. However, some methodological approaches which
could strengthen the analysis were not considered by the

Corrao 2006 1.70 (1.42, 2.03)

vanderLinden 2002 3.20 (2.09, 4.89)

Hori 2012 6.29 (2.27, 17.44)

Barge-Caballero 2008 1.37 (0.41, 4.58)

Daneman 2015 2.40 (2.24, 2.57)

Jupiter 2018 1.70 (1.48, 1.95)

Morales 2018 1.61 (1.25, 2.08)

Persson 2019 1.60 (1.22, 2.09)

Overall (I-squared = 84.5%, p = 0.000) 1.98 (1.62, 2.43)

NOTE: Weights are from random effects analysis

.0573 1 17.4

Fig. 4 Forest plot of the risk of ATD associated with fluoroquinolones

1442
authors, namely the stratification of the results according to
different outcomes (AT, ATR, or ATD), study designs and
methodological quality scores and risk windows.
Furthermore, some studies have not been included in the me-
ta-analysis, and the results of a retrospective cohort study con-
sidering both tendon and joint disorders as an outcome were
integrated into the risk estimate analysis, potentially increas-
ing the confounding among the final results [12].
Systematic reviews and meta-analyses of non-
experimental studies should be designed to explore
eventual sources of heterogeneity among the risk esti-
mates rather than to find evidence of causative associa-
tions [18]. With the exception of the subgroup analyses
according to different comparators, all the risk estimates
were associated with significant between-studies hetero-
geneity. These observational studies were conducted and
published over two decades. Therefore, these results
should be taken with precaution due to the inherent
methodological limitations faced when comparing stud-
ies conducted from different databases and associated
with varying size and precision [9]. Moreover, besides
the different demographics previously described, there
are additional methodological characteristics of the stud-
ies included in this meta-analysis which may not be
entirely comparable, namely the endpoint’ definition
and methods of diagnosis of tendon injuries, the valida-
tion of fluoroquinolones’ exposure, and the controlling
for confounding variables.
There are additional limitations which should be ad-
dressed. Most of the studies did not detail the risk esti-
mates by the type of fluoroquinolone and no sufficient
data was provided in order to assess if there is a dose-
response relationship associated with the development of
tendon injuries. Future research should address these is-
sues, since clinicians could benefit from such information
in order to minimize and prevent the risk of these adverse
effects [31]. Studies most frequently stratified their results
according to patient’s age and concomitant use of cortico-
steroids. However, additional risk factors for tendon inju-
ries were not considered, precluding additional sensitivity
analyses. Only three bibliographic databases were
searched. Since tendon injuries have been associated with
fluoroquinolones for so long, studies published in journals
indexed elsewhere may not have been identified through
this search strategy. A previous systematic review consid-
ered evidence from case series, cross-sectional, and sur-
veillance pharmacovigilance studies using spontaneous
reporting when assessing the risk of tendon injuries asso-
ciated with fluoroquinolones. However, the methodologi-
cal quality of such studies was considered to be very low
by the authors [10]. Therefore, in order to reduce the risk
of bias, other designs than case control and cohorts were
not considered for inclusion in this meta-analysis.
Eur J Clin Pharmacol (2019) 75:1431–1443
Conclusion
The results of this systematic review and meta-analysis sug-
gest that fluoroquinolones increase the risk of tendon injuries,
which is in line with the current knowledge. The use of these
antibiotics should be restricted since several subgroups of pa-
tients are at increased risk to develop serious tendon injuries,
particularly older patients and individuals under concomitant
treatment with corticosteroids. Moreover, patients should dis-
continue the treatment with fluoroquinolones and seek help
from healthcare professionals when they start feeling tendon
pain and inflammation.
Author contribution Carlos Alves conceived and designed the study,
performed research, analyzed data, and wrote the paper. Diogo Mendes
and Francisco Batel Marques conceived the study and wrote the paper.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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